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CORM-A1 Alleviates Pro-Atherogenic Manifestations via miR-34a-5p Downregulation and an Improved Mitochondrial Function

Atherogenesis involves multiple cell types undergoing robust metabolic processes resulting in mitochondrial dysfunction, elevated reactive oxygen species (ROS), and consequent oxidative stress. Carbon monoxide (CO) has been recently explored for its anti-atherogenic potency; however, the effects of...

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Autores principales: Vyas, Hitarthi S., Jadeja, Ravirajsinh N., Vohra, Aliasgar, Upadhyay, Kapil K., Thounaojam, Menaka C., Bartoli, Manuela, Devkar, Ranjitsinh V.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10215967/
https://www.ncbi.nlm.nih.gov/pubmed/37237862
http://dx.doi.org/10.3390/antiox12050997
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author Vyas, Hitarthi S.
Jadeja, Ravirajsinh N.
Vohra, Aliasgar
Upadhyay, Kapil K.
Thounaojam, Menaka C.
Bartoli, Manuela
Devkar, Ranjitsinh V.
author_facet Vyas, Hitarthi S.
Jadeja, Ravirajsinh N.
Vohra, Aliasgar
Upadhyay, Kapil K.
Thounaojam, Menaka C.
Bartoli, Manuela
Devkar, Ranjitsinh V.
author_sort Vyas, Hitarthi S.
collection PubMed
description Atherogenesis involves multiple cell types undergoing robust metabolic processes resulting in mitochondrial dysfunction, elevated reactive oxygen species (ROS), and consequent oxidative stress. Carbon monoxide (CO) has been recently explored for its anti-atherogenic potency; however, the effects of CO on ROS generation and mitochondrial dysfunction in atherosclerosis remain unexplored. Herein, we describe the anti-atherogenic efficacy of CORM-A1, a CO donor, in in vitro (ox-LDL-treated HUVEC and MDMs) and in vivo (atherogenic diet-fed SD rats) experimental models. In agreement with previous data, we observed elevated miR-34a-5p levels in all our atherogenic model systems. Administration of CO via CORM-A1 accounted for positive alterations in the expression of miR-34a-5p and transcription factors/inhibitors (P53, NF-κB, ZEB1, SNAI1, and STAT3) and DNA methylation pattern, thereby lowering its countenance in atherogenic milieu. Inhibition of miR-34a-5p expression resulted in restoration of SIRT-1 levels and of mitochondrial biogenesis. CORM-A1 supplementation further accounted for improvement in cellular and mitochondrial antioxidant capacity and subsequent reduction in ROS. Further and most importantly, CORM-A1 restored cellular energetics by improving overall cellular respiration in HUVECs, as evidenced by restored OCR and ECAR rates, whereas a shift from non-mitochondrial to mitochondrial respiration was observed in atherogenic MDMs, evidenced by unaltered glycolytic respiration and maximizing OCR. In agreement with these results, CORM-A1 treatment also accounted for elevated ATP production in both in vivo and in vitro experimental models. Cumulatively, our studies demonstrate for the first time the mechanism of CORM-A1-mediated amelioration of pro-atherogenic manifestations through inhibition of miR-34a-5p expression in the atherogenic milieu and consequential rescue of SIRT1-mediated mitochondrial biogenesis and respiration.
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spelling pubmed-102159672023-05-27 CORM-A1 Alleviates Pro-Atherogenic Manifestations via miR-34a-5p Downregulation and an Improved Mitochondrial Function Vyas, Hitarthi S. Jadeja, Ravirajsinh N. Vohra, Aliasgar Upadhyay, Kapil K. Thounaojam, Menaka C. Bartoli, Manuela Devkar, Ranjitsinh V. Antioxidants (Basel) Article Atherogenesis involves multiple cell types undergoing robust metabolic processes resulting in mitochondrial dysfunction, elevated reactive oxygen species (ROS), and consequent oxidative stress. Carbon monoxide (CO) has been recently explored for its anti-atherogenic potency; however, the effects of CO on ROS generation and mitochondrial dysfunction in atherosclerosis remain unexplored. Herein, we describe the anti-atherogenic efficacy of CORM-A1, a CO donor, in in vitro (ox-LDL-treated HUVEC and MDMs) and in vivo (atherogenic diet-fed SD rats) experimental models. In agreement with previous data, we observed elevated miR-34a-5p levels in all our atherogenic model systems. Administration of CO via CORM-A1 accounted for positive alterations in the expression of miR-34a-5p and transcription factors/inhibitors (P53, NF-κB, ZEB1, SNAI1, and STAT3) and DNA methylation pattern, thereby lowering its countenance in atherogenic milieu. Inhibition of miR-34a-5p expression resulted in restoration of SIRT-1 levels and of mitochondrial biogenesis. CORM-A1 supplementation further accounted for improvement in cellular and mitochondrial antioxidant capacity and subsequent reduction in ROS. Further and most importantly, CORM-A1 restored cellular energetics by improving overall cellular respiration in HUVECs, as evidenced by restored OCR and ECAR rates, whereas a shift from non-mitochondrial to mitochondrial respiration was observed in atherogenic MDMs, evidenced by unaltered glycolytic respiration and maximizing OCR. In agreement with these results, CORM-A1 treatment also accounted for elevated ATP production in both in vivo and in vitro experimental models. Cumulatively, our studies demonstrate for the first time the mechanism of CORM-A1-mediated amelioration of pro-atherogenic manifestations through inhibition of miR-34a-5p expression in the atherogenic milieu and consequential rescue of SIRT1-mediated mitochondrial biogenesis and respiration. MDPI 2023-04-25 /pmc/articles/PMC10215967/ /pubmed/37237862 http://dx.doi.org/10.3390/antiox12050997 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Vyas, Hitarthi S.
Jadeja, Ravirajsinh N.
Vohra, Aliasgar
Upadhyay, Kapil K.
Thounaojam, Menaka C.
Bartoli, Manuela
Devkar, Ranjitsinh V.
CORM-A1 Alleviates Pro-Atherogenic Manifestations via miR-34a-5p Downregulation and an Improved Mitochondrial Function
title CORM-A1 Alleviates Pro-Atherogenic Manifestations via miR-34a-5p Downregulation and an Improved Mitochondrial Function
title_full CORM-A1 Alleviates Pro-Atherogenic Manifestations via miR-34a-5p Downregulation and an Improved Mitochondrial Function
title_fullStr CORM-A1 Alleviates Pro-Atherogenic Manifestations via miR-34a-5p Downregulation and an Improved Mitochondrial Function
title_full_unstemmed CORM-A1 Alleviates Pro-Atherogenic Manifestations via miR-34a-5p Downregulation and an Improved Mitochondrial Function
title_short CORM-A1 Alleviates Pro-Atherogenic Manifestations via miR-34a-5p Downregulation and an Improved Mitochondrial Function
title_sort corm-a1 alleviates pro-atherogenic manifestations via mir-34a-5p downregulation and an improved mitochondrial function
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10215967/
https://www.ncbi.nlm.nih.gov/pubmed/37237862
http://dx.doi.org/10.3390/antiox12050997
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